Lung cancer is the leading cause of cancer death in both men and women in the US. While cigarette smoking is the major cause of lung cancer, only 10-20% of heavy smokers develop lung cancer. Because of the lack of effective biomarkers and the inability to identify which current and former smokers are at the greatest risk for developing cancer, lung cancer is most often diagnosed at a late state after it has spread; the five year mortality of lung cancer is 85%, a figure that has changed little over the past 3-4 decades. The goal of this project is to use airway gene expression profiles to develop a relatively non-invasive method for assessing risk of having tobacco-associated lung cancer. Our approach is based on the concept that cigarette smoke affects airway epithelial cells throughout the respiratory tract, thus producing an airway epithelial cell "field defect" that defines individual variations in the response to tobacco smoke and differentiates smokers with and without lung cancer. Using oligonucleotide gene expression arrays, experiments in this proposal will characterize the patterns of gene expression in epithelial cells obtained by brushing intrathoracic (lobar bronchi) airway in smokers with and without lung cancer. The impact of lung cancer on the airway transcriptome will be defined, along with gender and racial factors that influence epithelial cell damage in smokers with lung cancer. Using a number of class prediction algorithms, intrathoracic epithelial gene expression profiles that can be used to predict which smokers have lung cancer will be identified. Competitive PCR and matrix-assisted laser desorption ionization, time-of-flight, mass spectrometry will be used to confirm differential expression of selected genes identified in the array experiments. The long term objective of this study is to develop a non-invasive biomarker for lung cancer that can be tested in subsequent clinical trials to determine its value in identifying that subset of smokers who have, or are at risk for developing lung cancer.